PROJECT SUMMARY Salmonella enterica serovars Typhi and Paratyphi A (S. Typhi and S. Paratyphi A) are the predominant causes of enteric (typhoid/paratyphoid) fever globally, affecting over 11 million people and resulting in over 130,000 deaths each year. A small percentage of acutely infected individuals develop a chronic, but clinically asymptomatic infection in the biliary tract that can persist for decades. Since S. Typhi and Paratyphi A are human-restricted pathogens, chronic carriers may act as reservoirs of infection within a community, contribute to transmission through intermittent shedding of bacteria in feces and urine, and act as vehicles for introducing these organisms into previously uninfected communities. Therefore, correctly identifying and treating asymptomatic chronic carriers is critical for the long-term control of enteric fever. Currently, there are no optimal assays for identifying asymptomatic carriers. Here, we propose to address this deficiency and evaluate a novel biomarker of S. Typhi and Paratyphi A carriage. We have recently identified that antibodies targeting YncE (a putative ATP-binding protein) could accurately identify chronic carriers in a pilot study. Our proposal will include 3 complementary, but independent aims that will further characterize the diagnostic potential of this antigen and its value as an antigenic target for (1) community-based screening of carriage, (2) as a predictor of risk of developing carriage following acute disease, and (3) its use as a test of cure following elimination of carriage. In Aim 1, we will use a cross-sectional analysis to assess the prevalence of anti-YncE responses and carriage within a typhoid/paratyphoid endemic community. We will then apply a Bayesian latent class model to examine the utility of using serum anti-YncE responses as an effective screening tool to detect asymptomatic S. Typhi and S. Paratyphi A carriers at the community level. In Aim 2, we will perform a prospective cohort analysis to characterize the presence, persistence, and kinetics of antibody responses to YncE following acute infection and correlate responses with persistent shedding of S. Typhi or S. Paratyphi A. In Aim 3, we will characterize the presence, persistence, and kinetics of serum anti-YncE responses following elective cholecystectomy to determine if a fall in anti-YncE antibodies can be used as a test of cure. The results of this analysis could significantly inform typhoid control programs.